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Effects of Atomoxetine on the QT Interval in Healthy CYP2D6 Poor Metabolizers.


Br J Clin Pharmacol. 2012 Jul 16;


Authors: Loghin C, Haber H, Beasley CM, Kothare PA, Kauffman L, April J, Jin L, Allen AJ, Mitchell MI


Abstract

AIM: Effects of atomoxetine (20 and 60 mg twice daily), 400 mg moxifloxacin, and placebo on QTc in 131 healthy CYP2D6 poor metabolizer males were compared. METHODS: Atomoxetine doses were selected to result in plasma concentrations that approximated expected plasma concentrations at both the maximum recommended dose and at a supratherapeutic dose in CYP2D6 extensive metabolizers. Ten-second electrocardiograms were obtained for time-matched baseline on Days -2 and -1, three time points after dosing on Day 1 for moxifloxacin, and five time points on Day 7 for atomoxetine and placebo. Maximum mean placebo-subtracted change from baseline model-corrected QT (QTcM) on Day 7 was the primary endpoint. RESULTS: QTcM differences for atomoxetine 20 and 60 mg BID were 0.5 msec (upper bound of the 1-sided 95% confidence interval: 2.2 msec) and 4.2 msec (upper bound of the 1-sided 95% confidence interval: 6.0 msec), respectively. As plasma concentration of atomoxetine increased, a statistically significant increase in QTc was observed. The moxifloxacin difference from placebo met the a prori definition of non-inferiority. Maximum mean placebo-subtracted change from baseline QTcM for moxifloxacin was 4.8 msec and this difference was statistically significant. Moxifloxacin plasma concentrations were below concentrations expected from the literature; however, the slope of the plasma concentration-QTc change observed was consistent with literature. CONCLUSION: Atomoxetine was not associated with a clinically significant change in QTc. However, a statistically significant increase in QTc was associated with increasing plasma concentrations.

PMID: 22803597 [PubMed - as supplied by publisher]